The present invention relates generally to the area of lower respiratory tract infections. More particularly, the present invention provides a method for differentiating bacterial versus non-bacterial exacerbations of chronic lung disease.
Chronic bronchitis and other lung diseases including cystic fibrosis and bronchiectasis, are associated with intermittent exacerbations (such as acute exacerbations of chronic bronchitis (AECB)) that lead to worsening of the chronic symptoms of productive cough and dyspnea. These exacerbations cause considerable morbidity, and in patients with concomitant airway obstruction such as chronic obstructive pulmonary disease (COPD), are a major cause of mortality (Burrows et al., 1969, N. Engl. J. Med., 280:397-404). AECB can have one or more of several different etiologies (Sethi, 1998, Infect. Dis. Clin. Pract., 7:S300-S308). Virus infection, identified by a four-fold rise in antibody titer or by viral isolation, causes a third of exacerbations (Gump et al., 1976, Am. Rev. Respir. Dis., 113:465-473; Buscho et al., 1978, J. Infect. Dis., 137:377-383; Smith et al., 1980, Am. Rev. Respir. Dis., 121:225-232). Serological evidence of atypical bacterial infection, mostly by Chlamydia pneumoniae, is seen in 5-10% of exacerbations (Blasi et al., 1993, Eur. Respir. J., 6:19-22; Miyashita et al., 1998, Chest, 114:969-971). Bacterial pathogens, especially nontypeable Haemophilus influenzae, Streptococcus pneumoniae, Moraxella (Branhamella) catarrhalis and Pseudomonas aeruginosa are isolated from sputum in about 50% of exacerbations (Sethi, 1998, supra).
The role of bacterial pathogens as a cause of AECB is controversial for several reasons. Bacterial pathogens can be isolated from sputum during stable chronic bronchitis at the same frequency as during exacerbations. Serological studies examining antibodies to common bacterial pathogens and placebo-controlled antibiotic trials in AECB have yielded confusing and contradictory results. Though alternative explanations exist for these observations, many authors have interpreted them to show that bacterial pathogens play no role in AECB (Tager et al., 1975, N. Engl. J. Med. 292:563-571; Murphy et al., 1992, Am. Rev. Respir. Dis. 146:1067-1083; Isada, 1993, Antibiotics for chronic bronchitis with exacerbations. Seminars in Respiratory Infections. 8:243-253; Nicotra et al., 1993, Antibiotic use in exacerbations of chronic bronchitis. Seminars in Respiratory Infections. 8:254-258). This view holds that isolation of bacteria during AECB represents chronic colonization and is a mere epiphenomenon.
The absence of a more definitive and quick indication regarding the involvement of bacterial induced exacerbation of chronic lung disease makes the choice of treatment options difficult. Culturing of sputum to identify bacterial involvement is time consuming. Thus, there is an ongoing need for identifying markers that provide a simple and quick test to distinguish between different etiological causes of exacerbations of chronic lung disease, in particular to distinguish between bacterial and non-bacterial induced exacerbations.
The present invention provides a simple and quick test for discriminating between bacterial and non-bacterial exacerbations of chronic lung disease. The test is based on the unexpected observation of a strong correlation between bacterial AECB and sputum elastase. Thus, the test comprises obtaining a sputum sample from an individual such that it contains secretions of the lower respiratory tract, and testing it for the presence of elastase. For certain pathogens, a correlation is also observed between AECB and sputum IL-8 or TNF-xcex1. Thus, in another embodiment, the levels of IL-8 or TNF-xcex1 may be tested. The amount of these markers is then compared to standard reference. The comparison may be done using a calorimeter or by visual means.